Accumulation of pathogenic proteins and peptides with expanded polyglutamine repeats is characteristic of Huntington's disease (HD) and related neurodegenerative diseases. Other than the fact that a polyQ expansion within the disease protein causes disease, the major cellular mechanisms of pathogenesis are not clear. Multiple cellular processes have been implicated, but proximal causative events have proven difficult to distinguish from distal correlative events. As polyQ disease proteins can be modified in ways that change their cellular function or fate, it is likely that Htt protein modifications contribute to pathology. We find that Htt can be SUMO modified and that this modification can affect its biochemical properties and pathogenic potential in a Drosophila model. These observations form the rationale for this proposal. I propose to investigate, in depth, the role of SUMOylation in HD pathogenesis and to investigate the biochemical mechanisms involved in the SUMO-1 modification and de-SUMOylation of mutant Htt using a multidisciplinary approach. Implicit in this research will be an effort to identify potential therapeutic targets and develop strategies for interventions that disrupt or prevent pathology in the biochemical pathways responsible for alteration of mutant Htt. Hypothesis 1: SUMO modification of Htt is involved in HD phenotypes Mutant Htt accumulates in the nuclei of neurons and induces the dysregulation of key cellular processes including transcription. The impact of SUMOylation of mutant Htt upon cellular functions will be tested using in vitro and in vivo systems. Hypothesis 2: Specific E3-SUMO ligases are responsible for SUMO modification of Htt. An overall reduction of SUMOylation suppresses pathogenesis in vivo, therefore the identification of the specific enzymes involved in the attachment of SUMO groups to the Htt protein or in the removal of SUMO from the Htt protein may provide novel therapeutic targets for treatment of HD. Hypothesis 3: SUMO modification of Htt is critical to disease pathogenesis in vivo. Here we will test the physiologic relevance of SUMO modification pathways in Drosophila.